There has been a long-standing interest in gaining further insights into rare tumors whose etiology is poorly understood. At present, this project is focusing the majority of efforts on three tumors--nasopharyngeal, biliary and liver cancers. Nasopharyngeal cancer (NPC)has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer, other factors, both genetic and exogenous, are also thought to be important. To investigate genetic, dietary, occupational, and behavioral factors related to the etiology of NPC, a case-control study was conducted in Taiwan. To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1, HLA, smoking and micronutrients. High intakes of nitrosamines and nitrite during childhood and weaning also were associted with increased risks. Occupational exposures to formaldehyde, solvents, wood dusts, and nitrosamines are currently under investigation. A large-scale linkage study is now under way in Taiwan to enable a careful and systematic assessment of genetic and environmental determinants of this cancer. During the last 25 years, biliary tract cancer incidence has increased more rapidly than any other malignancy in Shanghai. The sharply rising trend suggests a change in the prevalence of risk factors. To elucidate these factors, we are nearing completion of a large scale population-based case-control study to investigate the role of gallstone, bacterial infections of the biliary tract, dietary factors, obesity, use of tobacco and alcohol, reproductive factors, and exogenous hormones. With 1,000 cancer cases in the study, there will be sufficient statistical power to examine the etiology separate for each subsite. Since gallstone disease tends to cluster in families, attempts will be made to evaluate whether genetic predisposition plays a role in biliary tract cancer, through analysis of family history and testing for polymorphisms of susceptibility genes as well as interactions with lifestyle factors. The incidence of liver cancer has striking geographic variability with the vast majority of cases arising in southeast Asia and sub-Saharan Africa. While some risk factors for liver cancer in these areas are well established, the risk of developing liver cancer is not uniformly distributed among even high-risk individuals. To examine whether genetic susceptibility influences risk, we have been collaborating with a large prospective study being conducted in Haimen City, China. In this population, hepatitis B virus infection and aflatoxin exposure have been the major risk factors. Nested case-control investigations have examined variants among loci that are in the aflatoxin B1 metabolism pathway (primarily the GST and EPHX families) and have found evidence that variants in the EPHX family may be critical to genetic susceptibility. These findings are being followed up in a family analysis that includes the first and second degree relatives of the case-control probands. In addition, we are prospectively examining the effect of homocysteine and B vitamins (folate, vitamin B6, vitamin B12) and their related genetic loci on viral status of the population and intermediate markers of liver damage. More novel analyses of exposure to organochlorines, microcystins and fumonisins are being planned. In an effort to determine whether medical conditions associated with westernization (e.g., diabetes and obesity) are related to the development of liver cancer, we are conducting a record linkage case-control study in which information on prior medical conditions as recorded in inpatient records is being accessed.